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MiR-126 regulates glycogen trophoblast proliferation and DNA methylation in the murine placenta.

ABSTRACT: A functional placenta develops through a delicate interplay of its vascular and trophoblast compartments. We have identified a previously unknown expression domain for the endothelial-specific microRNA miR-126 in trophoblasts of murine and human placentas. Here, we determine the role of miR-126 in placental development using a mouse model with a targeted deletion of miR-126. In addition to vascular defects observed only in the embryo, loss of miR-126 function in the placenta leads to junctional zone hyperplasia at E15.5 at the expense of the labyrinth, reduced placental volume for nutrient exchange and intra-uterine growth restriction of the embryos. Junctional zone hyperplasia results from increased numbers of proliferating glycogen trophoblast (GlyT) progenitors at E13.5 that give rise to an expanded glycogen trophoblast population at E15.5. Transcriptomic profile of miR-126-/- placentas revealed dysregulation of a large number of GlyT (Prl6a1, Prl7c1, Pcdh12) and trophoblast-specific genes (Tpbpa, Tpbpb, Prld1) and genes with known roles in placental development. We show that miR-126-/- placentas, but not miR-126-/- embryos, display aberrant expression of imprinted genes with important roles in glycogen trophoblasts and junctional zone development, including Igf2, H19, Cdkn1c and Phlda2, during mid-gestation. We also show that miR126-/- placentas display global hypermethylation, including at several imprint control centers. Our findings uncover a novel role for miR-126 in regulating extra-embryonic energy stores, expression of imprinted genes and DNA methylation in the placenta.

SUBMITTER: Sharma A

PROVIDER: S-EPMC6451886 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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miR-126 regulates glycogen trophoblast proliferation and DNA methylation in the murine placenta.

Sharma Abhijeet A Lacko Lauretta A LA Argueta Lissenya B LB Glendinning Michael D MD Stuhlmann Heidi H

Developmental biology 20190214 1

A functional placenta develops through a delicate interplay of its vascular and trophoblast compartments. We have identified a previously unknown expression domain for the endothelial-specific microRNA miR-126 in trophoblasts of murine and human placentas. Here, we determine the role of miR-126 in placental development using a mouse model with a targeted deletion of miR-126. In addition to vascular defects observed only in the embryo, loss of miR-126 function in the placenta leads to junctional ...[more]

PMID: 30771304

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Project description:BackgroundEmerging evidence has identified miR-138 as a tumor suppressor that can suppress the proliferation of various cancers. Meanwhile, the cause of abnormal miR-138 expression in cervical cancer remains uncertain. This study clarified the mechanism by which miR-138 regulates proliferation, invasion, metastasis, and EMT in cervical cancer cells.ResultsmiR-138 expression in human cervical cancer and adjacent normal tissue was measured using qPCR. SiHa and C33A cells were used to determine the function of miR-138 via miR-138 mimic or inhibitor transfection, followed by wound healing, Cell Counting Kit-8, flow cytometry, and Transwell assays. Epithelial and mesenchymal marker expression was analyzed using Western blotting. DNA methylation in the miR-138 promoter was examined using bisulfite sequencing PCR. The downstream target genes of miR-138 were identified via bioinformatics analysis and luciferase reporter assays. A tumor xenograft model was employed to validate DNA methylation-induced miR-138 downregulation and tumor growth inhibition in cervical cancer in vivo. miR-138 levels were significantly lower in cervical cancer tissues than in adjacent control tissues. Furthermore, lower miR-138 expression and higher CpG methylation in the miR-138 promoter were identified in lymph node-positive metastatic cervical cancer tumors versus that in non-metastatic tumor tissues. Upon miR-138 overexpression, cell proliferation, metastasis, invasion, and EMT were suppressed. miR-138 agomir transfection and demethylating drug treatment significantly inhibited cervical tumor growth and EMT in tumor xenograft models. DNA methylation inhibited miR-138 transcription, and enhancer of zeste homolog 2 (EZH2) downregulation mediated the tumor suppressor function of miR-138 in cervical cancer.ConclusionWe demonstrated that miR-138 suppresses tumor progression by targeting EZH2 in cervical cancer and uncovered the role of DNA methylation in the miR-138 promoter in its downregulation. These findings demonstrated the potential of miR-138 to predict disease metastasis and/or function as a therapeutic target in cervical cancer.

Dataset Information

MiR-126 regulates glycogen trophoblast proliferation and DNA methylation in the murine placenta.

Publications

miR-126 regulates glycogen trophoblast proliferation and DNA methylation in the murine placenta.

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